text:
Home Blog Advanced Nutrition for the Growing Horse
Advanced Nutrition for the Growing Horse
Many people question how to provide their horses with all of the nutrition, vitamins, minerals, and protein they need without going over their calorie limit, which could lead to problems later. Especially when it comes to weanlings, it might be difficult, but not impossible, to feed a horse a well-balanced diet. To avoid difficulties with skeletal growth, always check your horse's physical condition and weight, and make sure there aren't any high hormonal swings. Consumption of starch and sugar should be kept to a minimum.
Instead, for a healthy diet, provide pasture and hay as a free-choice option. When you give your horse access to pasture, you're giving more than just vitamins and minerals; you're also giving a chance to exercise and move around, which helps grow musculoskeletally by strengthening cartilage. Omega-3 fatty acids should be the most significant portion of their diet for bone mineral content, density, strength, and growth.
The nutritious start a foal receives can have a significant impact on its long-term health and well-being. We can accelerate growth if we so desire. However, evidence suggests that a well-balanced diet that supports just a moderate pace of change is less likely to produce developmental issues.
Here's what kind of equine supplies in Dubai that you can additionally give to your horse to ensure proper growth rate and nutrient balance
Essential Nutrients for Foals: Royal Horse B-150
Royal Horse B-150 promotes good digestive health, foal growth and supports the reproductive system. It is supplemented with Prebiotics, L-Carnitine and Omega 3. This Stud line is developed to strengthen immunity, facilitate foal weaning, and optimize broodmare fertility and lactation.
Standard Ration for a Broodmare Weighing 500 Kg
Gestating (before eight months)
B-150: 2 to 3 kg (4.5 to 6.7 litres) and hay 5 kg
Gestating (8 to 11 months)
B-150: 4 to 5 kg (8.9 to 11 litres) and hay 5 kg
Lactating (first three months after foaling)
B-150: 6 to 8 kg (13 to 17.7 litres) and hay 5 to 7 kg
Pre-Weaning
First month
B-150: 0.5 kg (1.1 litres) of B-150 then add 0.5 kg per month.
Post-Weaning
B-150: 2 to 4kg (6.5 to 9 litres) and hay 3kg
B-150: 3.5 to 4.5 kg (7.7 to 10 litres) and hay 4kg
Standard Ration for a Stallion Weighing 500 Kg
Covering Season
B-150: 4 to 5 kg (9 to 11 litres) and hay: 5 kg
Outside Covering Season
B-150: 2 to 3 kg (4.5 to 6.5 litres) and hay: 5 kg
Essential Nutrients to Cover the Needs of Horses and Ponies Fed on Cereal and Forge: Royal Horse C-200
Royal Horse C-200 promotes good digestive health, improves ration balance and resolves deficiencies in cereal-based rations. It is supplemented with prebiotics, high protein content and contains a mix of minerals and vitamins.
Standard Ration for a Horse Weighing 500 Kg Competition Horses
C-200: 1 kg (1.5 litres), cereals: 3 to 4 kg and hay: 6 kg
Sport & Leisure Horses
C-200: 0.5 kg (0.8 litres), cereals: 2 to 3 kg and hay: 6 kg
Stud Horses
Foals (from the first few weeks of life until weaning): C-200 & cereals: 300 g (0.45 litres)
From Weaning Up To 12 Months
C-200: 1.5 to 2 kg (2.3 to 3 litres), hay: 2 to 4 kg, hay: 2 to 3 kg
C-200: 850 g to 1.3 kg (1.3 to 2 litres),
cereals: 2 to 2.5 kg, hay: 5 to 6 kg
Broodmares (last three months of gestation)
C-200: 750 g to 1 kg (1.1 to 1.5 litres) cereals: 2 to 2.5 kg, hay: 5 to 6 kg
Lactating mares
C-200: 2 kg (3 litres), cereals: 4 to 5 kg, hay: 6 to 7 kg
C-200: 1 to 2 kg (1.5 to 3 litres) Cereals: 2 to 3 kg, hay: 6 to 7 kg (depending on whether it is covering season or not)
While Equine supplies are available around, it is very important to get the best horse feed in Dubai. The internationally renowned brand Royal Horse feed in Dubai is brought to you by the leading suppliers eurovets Dubai.


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Home Food service O'Briens Irish Sandwich Cafe Wins Praise for New Cage-Free Egg Goal
O'Briens Irish Sandwich Cafe Wins Praise for New Cage-Free Egg Goal
Tan Heng Hong
KUALA LUMPUR, Malaysia, Nov. 21, 2022 /PRNewswire/ — Popular sandwich chain O'Briens Irish Sandwich Cafe won praise today from international NGO Lever Foundation for its new pledge to source only cage-free eggs by 2025 for its shops in Malaysia and elsewhere in Asia.
Headquartered in Dublin, Ireland, O'Briens runs over 200 cafes worldwide, including 25 outlets in Malaysia and additional stores in mainland China, Australia, Singapore and Dubai Airport. Under the new goal, O'Briens Irish Sandwich Cafe shops in APAC will source only cage-free eggs by 2025.
"We firmly believe that the food we consume every day is the foundation of a healthy lifestyle, which is why we pride ourselves on choosing premium ingredients for our signature dishes," said Brian Pua, Managing Director at O'Briens Irish Sandwich Cafe. "For this reason, we feel the time is right for a full commitment to using only cage-free egg ingredients in our cafes in Malaysia and APAC by 2025, as a way to making our supply chain kinder to animals and healthier for consumers."
"We congratulate O'Briens Irish Sandwich Cafe for this excellent cage-free pledge, which will greatly benefit egg-laying hens as well as domestic and international customers," said Vilosha Sivaraman, Sustainability Program Manager at Lever Foundation, which worked with the company on its commitment. "We hope more restaurant chains and food companies in Malaysia follow O'Briens' example in ending the use of caged eggs."
Animal protection and food safety organizations worldwide encourage a switch to cage-free eggs, which are more humane to animals and safer for consumers. Research by the European Food Safety Authority and others has found that cage-free egg farms are up to 25 times less likely to be contaminated with key salmonella strains than hens raised in cages.
A study by Universiti Putra Malaysia (UPM) found that the humane treatment of animals is a critical component of the country's growing green foods movement, with 91% of consumers believing green foods can and must prevent unnecessary animal suffering. A separate study also showed consumers are willing to pay significantly more for higher-quality eggs.
About Lever Foundation
Lever Foundation is a global NGO that works with leading food companies in Malaysia and across the region to help them upgrade their protein sourcing for a more humane, safe and sustainable supply chain.
O'Briens
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Uncle Bob Launches New Harvest Gourmet Menu
Tan Heng Hong - 21st September 2022 0
New Menu to Feature Nestlé's Harvest Gourmet Nuggets and Schnitzel KOTA KINABALU, September 2, 2022 – Marking Nestlé Malaysia's continued expansion of its plant-based meal solutions...
Mytea with no sugar launched in Indonesia
Tan Heng Hong - 23rd May 2022 0
PT Suntory Garuda Beverage has released Mytea + No Sugar in Indonesia. The RTD tea contains Oolong Tea Polymerized Polyphenols (OTPP). According to Suntory,...
New Jukajo Kids deliver plant-based nutrients for children aged 7 months...
Kickapoo in two new limited edition flavours
Ichitan rolls out vitamin fortified RTD tea

redpajama_set_name: RedPajamaCommonCrawl


text:
Tour News
Barry Lane wins British Par 3 Championship
Jeremy Ellwood
17 years after first being invited to the Farmfoods British Par 3 Championship, Barry Lane finally teed it up… and promptly walked off with the winner's cheque
Farmfoods British Par 3 host, Tony Jacklin, presents the trophy to Barry Lane
No lead could ever be considered safe around the compact, but decidedly tricky little course at Nailcote Hall, where 56 professionals have been competing for the Farmfoods British Par 3 Championship over the past couple of days in a pro-am format.
But yesterday's excellent six-under round of 48 gave British Par 3 newcomer, Barry Lane, just enough of a cushion to see off the chasing pack, led by short-game specialist, Paul Lawrie, who shot a record 46 in this event last year.
Earlier in the day, Gary Wolstenholme had matched Lawrie's 46 from last year, cramming eight birdies and no dropped shots into a round that was 15 shots better than his opening effort on Wednesday.
That spectacular effort saw him climb into a tie for 3rd on one-under with two Andrews – Sherborne and Marshall.
Those five were the only players under par after two days – testament to the challenge presented by a course that only just tiptoes over 2,000 yards for 18 holes.
Lane couldn't match his fireworks of yesterday in round two, but three birdies early on the back nine proved vital, as he would go on to drop shots on both 17 and 18 while Lawrie played the final two holes in one-under. But he couldn't deliver the closing birdie required to force a play-off.
Lane ended up on five-under after a round of 55, and Lawrie one shot behind after a closing 53.
"The course was fantastic," said Lane "Paul didn't make it easy, especially towards the end but I was confident that I could hold on. It was a wonderful tournament and I'd love to come back to defend my title next year."
Winner, Barry Lane, with the spoils of victory
VIDEO: Barry Lane reflecting on his career…
Ladies European Tour star, Charley Hull, also made an early charge in the final round with four birdies in her first five holes, but was unable to keep it going and eventually finished tied 9th, alongside Wentworth's Tom Reid who Tony Johnstone and I had the pleasure of playing with.
A poor shot on the 13th seemed to inspire Reid, for having got up and down there after clattering an advertising hoarding, he birdied three of his last five holes to make a big climb up the leaderboard, rounding things off with an impressive 25-footer on 18 in front of an appreciative crowd.
Host and two-time Major winner, Tony Jacklin CBE, was on hand to present the prizes, including the £25,000 first prize to Lane. The Norma C Herd Silver Salver for leading amateur went to 13-year-old Jack Drury with a score of +8.
Carl Mason, who is the highest career money winner on the European Senior Tour, scooped the £5,000 Super Senior prize for the third year running, finishing on level par. The leading team prize was also won by Barry Lane and his playing partner, David Nelson. The pair finished on 14-under.


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Matt Williams is an English rugby 7s international and player. He has played in the RFU Championship for London Scottish where he was a prolific try scorer, Moseley, Bristol Rugby  Sale Sharks and Doncaster Knights.

He attended The John Fisher School in Purley, Surrey; a senior all boys Roman Catholic day school.

References

External links
Stabunker profile

English rugby union players
Moseley Rugby Football Club players
Living people
Year of birth missing (living people)

redpajama_set_name: RedPajamaWikipedia


Oil Painting for Starters: Oil painting is actually surprisingly easy! But the equipment list can be daunting – so at Limetrees Studio, all your equipment is supplied as part of the course. These are 2 session courses on Tuesday mornings, or occasional Saturdays. There are also some weekend workshops.
I teach art-based workshops for calligraphers at societies around the country.
I've taught in South Africa, Belgium, UK and Australia. I love teaching enthusiastic beginners and empowering people by tapping into their creativity. Here is a list of typical workshops; you're welcome to choose from this selection or I would be happy to design a workshop based on your group's needs. If you Browse the Blog archive in the right hand column, under the correct month (and page), you'll find out more about actual workshops that have been run.
Uncials: the best initial introduction to calligraphy. It's accessible and you learn pen control.


Use the toolbar to the right to view the Future Leaders' Initiative, which contains resources and tools for doctoral scholars and faculty in early intervention, special education, and related services.
This webinar focused on Personnel Development to Improve Services and Results for Children with Disabilities: Interdisciplinary Preparation in Special Education, Early Intervention, and Related Services for Personnel Serving Children with Disabilities who have High-Intensity Needs (84.325K).
Fiscal Year 2019: Personnel Development to Improve Services and Results for Children with Disabilities (CFDA 84.325).
This is the Grant Performance Report for Continuation Funding. For specific guidance on how to write and report data on your program and project measures, please contact your Project Officer.
This Toolkit was designed to provide evaluation resources for grantees of OSEP's Personnel Development Program, but it contains useful information for other grantees as well. The Toolkit is not intended to provide a lengthy discussion of every aspect of project evaluation. Rather, it is designed to highlight important issues to consider when planning and conducting a PDP project evaluation—with a specific focus on summative evaluation—and to offer a variety of resources related to evaluation, including sample templates and forms, links to professional standards and other educator resources, and recommended readings on research and evaluation.
Under the Government Performance and Results Act (GPRA), the Department of Education has established a set of performance measures that are designed to yield information on various aspects of the effectiveness and quality of the Personnel Development to Improve Services and Results for Children with Disabilities program.
Measure 1: The percentage of preparation programs that incorporate scientifically or evidence-based practices into their curricula.
Measure 2: The percentage of scholars completing preparation programs who are knowledgeable and skilled in evidence-based practices for children with disabilities.
Measure 3: The percentage of scholars who exit preparation programs prior to completion due to poor academic performance.
Measure 4: The percentage of scholars completing preparation programs who are working in the area(s) in which they were prepared upon program completion.
Measure 5: The Federal cost per scholar who completed the preparation program.
Outcome Measure 1: The percentage of scholars who completed the preparation program and are employed in high-need districts.
Outcome Measure 2: The percentage of scholars who completed the preparation program and are employed in the field of special education for at least two years.
Outcome Measure 3: The percentage of scholars who completed the preparation program and are rated effective by their employers.
Data that grantees, scholars and employers submit through the Data Collection System are used to report on Measures 2 through 5 and the three outcome measures.


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Alan Rickman Dead at 69
Best known for playing Professor Snape in "Harry Potter" and Hans Gruber in "Die Hard," Alan Rickman died at 69 of cancer in London on Thursday.
byRiyan Septa
One of the most beloved actors in England, stage and big screen performer Alan Rickman died at 69 in London on Thursday. Rickman's family said in a statement that the cause of his death was cancer.
Rickman was born in London to a working class family in 1946 and educated in acting at the prestigious Royal Academy of Dramatic Art.
Rickman then became one of the most famous British actors with a long career over the last 30 years. Rickman won an Emmy and a Golden Globe for his role as a crazed monk in HBO's Rasputin: Dark Servant of Destiny in 1996.
Rickman debuted successfully when acting as a stage performer with the Royal Shakespeare Company at 1985-production Les Liaisons dangereuses.
Rickman then played in a variety of roles for big screens. Rickman often played as a villain in films such as Die Hard and Harry Potter series in which he won many new fans for his role as Professor Severus Snape.
Rickman's last films are including The Butler as Ronald Reagan and Alice Through the Looking Glass as Absolem the Caterpillar.
Daniel Radcliffe, the protagonist of Harry Potter film series, described Rickman as an extremely kind, generous, self-deprecating, funny guy.
"Alan Rickman is undoubtedly one of the greatest actors I will ever work with. He is also, one of the loyalest and most supportive people I've ever met in the film industry," Radcliffe said in a statement posted online.
Rasputin: Dark Servant of Destiny
Royal Academy of Dramatic Art
Riyan Septa
How To Be Single: Upcoming Film Starring Dakota Johnson Attempts to Explain it All
Khloé Kardashian: Lamar Odom Is a Sex Addict
Jharrel Jerome wins first Emmy for heart wrenching performance in When They See Us
The 71st Primetime Emmy Awards was full of pleasant victories as Bronx native Jharrel Jerome took home his…
byAshly E. Smith
Viola Davis Responds to the New York Times Article Calling Her Ugly
The New York Times created a stir by basically calling Viola Davis ugly by comparing her looks to Kerry Washington. Viola Davis offers up a classic response.
DMC Shows Love at the Black Comic Book Festival in Harlem
DMC joined roughly 5,000 blerds at the Black Comic Book Festival in Harlem on Saturday, Jan. 16.
byVictoria Johnson
Roger Moore: Idris Elba Can't be James Bond as 007 Should be 'English-English'
Apparently Idris Elba can't be James Bond because he isn't "English-English" in one former Bond's eyes.


text:
/*
	Project 4-1

	Demonstrate the finalize() method.
*/
class FDemo {
	int x;

	FDemo(int i) {
		x = i;
	}

	// called when object is recycled
	protected void finalize() {
		System.out.println("Finalizing " +x);
	}

	// generates an object that is immediately destroyed
	void generator(int i) {
		FDemo o = new FDemo(i);
	}
}

class Finalize {
	public static void main(String args[]) {
		int count;

		FDemo ob = new FDemo(0);

		/*
			Now, generate a large number of objects.

			At some point, garbage collection will occur.

			Note: you might need to increase the number of objects generated in order to force garbage collection.
		*/

		for(count=1; count < 100000; count++)
			ob.generator(count);
	}
}

redpajama_set_name: RedPajamaGithub


We are currently working hard with the National Piping Centre for setting up IBC 2016.
But first, IBD 2015 is round the corner with lots happening in the world!
Glasgow - The National Piping Centre will be live streaming a concert online. Watch out for the video on their website.
Chester - Chester pipers are organising an IBD session with many different pipes at the Cross Keys.
Berlin - Swedish piper Olle Gällmo is playing for a Bal Folk at the Haus der Sinne in Berlin, Germany. The band Sunday Jam will also be playing with Matthias Branschke on the pipes.
Athens - The Greek pipers will gather for a picnic on Philopappou hill opposite the Acropolis. Their slogan is "in days like these, all we need is each other", so feel free to join them!
Santorini - La Ponta, the tsambouna centre in Santorini is celebrating International Bagpipe Day.
Budapest - Hungarian pipers are joining the festivities by celebrating IBD at their regular club event.
Iran - Iranian bagpiper Mohsen Sharifan has organised concerts and a bagpipe competition which ends on 10 March. Many photos can be found on their instragram page.
Thunder Bay - Canadian pipe band THE Pipes and Drums of Thunder Bay have a whole day planned with fun piping events, including a radio appearance, a photo competition and an evening performance.
Texas - Texas Tech Uni will be carrying out a bagpipe programme during the day and Carlos Nuñez will be performing in the evening.
Chicago - Patrick Cannady will be playing the uilleann pipes at Johnny O'Hagan's. Why not join him for a tune and a drink?
Detroit - The Purcell Irish Pipers of Detroit will be celebrating in style with uillean pipes.
Minsk - Belarus is celebrating Spring and pipes on 11 March in Minsk with a big folk dance.
Leuven - Belgian pipers have got together and are organising a symposium focused on bagpipe education around Europe. Their event is online here.


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Q: Two equivalent Working Copies in xCode project In my project I suddenly got two equivalent Woking Copies

In file xcshareddata/1f-messenger.xccheckout I see duplicates. But as I understand this file
is made at each opening of the project and it is useless to try to modify it.
The most annoying thing is that when I try to pull data from remote git xCode shows me two equivalent repositories one of which is forbidden because of local code change until a commit.
I suspect that problem is due to some path corruption. One can see the fragment of 1f-messenger.xccheckout
<key>IDESourceControlProjectRelativeInstallPathDictionary</key>
<dict>
    <key>9CAC6304-4358-41CD-9DFC-AAB679FD18F6</key>
    <string>../../../../../../../../users/malex/Work/Git/1Forma/1f-messenger</string>
    <key>CE5489EB-6E76-493B-AD14-F8FB23B31539</key>
    <string>../..</string>
</dict>

I monitored all git configs, made new clone of my repo. But it seems that this is a problem of xCode itself.
The problem arose when I made a copy of the project locally and opened copy in xCode.
Now I have no any project copies on disk.

A: It is amazing but this problem is cured by ordinary osx reboot!
Note that reopen of xCode even after project "delete" and "clone" doesn't affect situation.

redpajama_set_name: RedPajamaStackExchange


Used in building structures, cabinets, and enclosures, BG(TM) cable entry system is designed to seal large quantities of metal clad or armored cables using minimal space. Adaptable product can directly replace conventional cable glands and provides additional protection against weather, blast, rodents, and fire. Users can seal varying ODs of single or multiple cables while ensuring certified bonded or grounded termination.


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Give a gift to the environment!
2023 Environmental Summit
Tickets are still available for CTLCV Education Fund's 2023 Environmental Summit, which will be held on Tuesday, January 24th from 9:30am - 3:30pm at the Connecticut Science Center in Hartford. CLICK HERE to find out more details and register for this event today!
The Connecticut League of Conservation Voters (CTLCV) is a non-partisan, statewide, nonprofit organization dedicated to giving our environment a voice at the Capitol.
We work to elect champions who will fight for the air we breathe, water we drink, and values we share. During session, we inform lawmakers and the public about key environmental priorities, track critical votes, and hold our leaders accountable. Check out our newly released 2022 Scorecard!
Learn how your lawmakers voted on environmental issues during the legislative session.
2022 Environmental Legislative Results
See the progress on key environmental bills as they move through the legislature.
Join CTLCV and help us protect the air we breathe, water we drink, and future we believe in!
2022 ENVIRONMENTAL LEGISLATIVE DEBRIEF
SEE PICTURES FROM THE 2022 ENVIRONMENTAL ACHIEVEMENT AWARDS
Endorse and elect candidates who will fight climate change and protect our environment.
Track key environmental bills in the General Assembly and record lawmakers' votes.
Alert lawmakers and citizens on key actions they can take to protect our environment.
Stay On Top of
CT-N
CT Capitol Report
Earth Week 2021 Events
Earth Day 2021 highlights the need to Build Back Better when it comes to environmental issues. When the world returns to normal, we cannot return to our normal ways of operating that pollute the environment and perpetuate environmental injustice. This year, CT RENEWS hosted a virtual lobby day to advocate for major environmental justice bills. On Earth Day, a socially distant gathering will be held at the CT State Capitol to highlight the hard work done towards modernizing the Bottle Bill. Participants are encouraged to bring empty bottles collected in litter clean-ups as visual aids.
Governor's Council on Climate Change
In September 2019, Governor Lamont issued Executive Order #3 to bring Connecticut to a 100% zero-carbon electric grid by 2040 and reinstate the Governor's Council on Climate Change. Over the past year, the working groups of the GC3 have pulled together reports providing the most effective recommendations to mitigate and adapt to climate change. Now is our opportunity to comment on those reports!
Every year, CTLCV Education Fund brings together lawmakers, advocates, policy experts, and members of the public for an informative look at the key environmental issues facing the General Assembly in the upcoming session. The 2021 Summit was held in January. Take a look at our Summit page for all the materials and information.
Always Know the Score
During the legislative session, CTLCV tracked key environmental and clean energy votes. Now we've done the math and graded how our lawmakers voted on the issues that matter most.
We've identified important environmental champions as well as lawmakers who are out of step with the environment. You can also see summaries of the bills we scored, an analysis of what passed, and predictions about what we can expect in the upcoming session.
Clean Energy for All Begins in Connecticut
Climate change is THE issue of our generation, and clean energy is key to winning the fight. Join CTLCV in calling on our lawmakers to make sure Connecticut invests in 100% clean energy by 2050 or sooner.


text:
tert-butyl α,α-dimethylbenzyl peroxide
EC number: 222-389-8 | CAS number: 3457-61-2
Currently viewing: 001 Key | Experimental result002 No specified study adequacy | No specified result type
screening for reproductive / developmental toxicity
other: GLP guideline study
Reason / purpose:
reference to same study
short-term repeated dose toxicity: oral
supporting study
other: Non GLP dose-range finding study, well documented for the purpose.
no guideline followed
Dose range finding study, 14 days exposure by oral route.
- Source:Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy.
- Age at study initiation: 27-29 days old
- Weight at study initiation: 75-99 g
- Housing: 5 of one sex to a cage
- Diet and water ad libitum:
- Acclimation period: 12 days
- Temperature (°C): 22°C +-2°C
- Humidity (%): 55% +-15%
- Air changes (per hr): 15 to 20 air change
- Photoperiod (hrs dark / hrs light): 12/12
Details on oral exposure:
The test item was administered orally by gavage at a dose volume of 5 mL/kg body weight. Control animals received the vehicle alone at the same dose volume.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The formulation was prepared daily (concentrations of 20, 60 and 200 mg/ml).
Duration of treatment / exposure:
Frequency of treatment:
Dose / conc.:
100 mg/kg bw/day (nominal)
1 000 mg/kg bw/day (nominal)
yes, concurrent vehicle
The following investigations were performed: clinical signs, body weight and food consumption. In addition, selected organs were collected and weighed and post mortem macroscopic and microscopic examinations were performed.
Observations and examinations performed and frequency:
Throughout the study, all animals were checked early in each working day and again in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day. All clinical signs were recorded for individual animals.
Once before commencement of treatment and once daily during treatment, each animal was observed and any clinical signs were recorded. Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions. Observation of the cage tray was also performed starting from Day 4 of treatment. Each animal was weighed on the day of allocation to treatment group, on the day that treatment commenced, weekly thereafter and just prior to necropsy. The weight of food consumed by each cage of rats was recorded at weekly intervals, following allocation. The group mean daily intake per rat was calculated.
Sacrifice and pathology:
See tissue procedure table in the attached document.
Other examinations:
Histopathological examination was performed since potential treatment-related changes were observed in liver, kidney and thymus at macroscopic examination and organ weights evaluation. As suggested by the Study Pathologist and in agreement with the Sponsor, the histopathological examination of these tissues was performed for all groups.
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
Ophthalmological findings:
Haematological findings:
Clinical biochemistry findings:
Urinalysis findings:
Behaviour (functional findings):
Organ weight findings including organ / body weight ratios:
Description (incidence and severity):
Liver, kidney. See below for more details.
Gross pathological findings:
The most relevant changes at post mortem examination, detected in treated animals when compared with their controls, consisted of swollen and/or enlarged and/or firm liver in males and females dosed at = 300 mg/kg/day.
Histopathological findings: non-neoplastic:
At 1000 mg/kg/day in male liver: minimal to mild increased size of hepatocytes, including nucleus and cytoplasm, localised in the centrilobular region of the hepatic lobule.
Details on results:
Dertails on organ weight: A statistically significant increase of absolute and relative liver weight was detected in males and females dosed at = 300 mg/kg/day. A statistically significant increase of relative kidney weight was also observed in males dosed at = 300 mg/kg/day and females dosed at 1000 mg/kg/day. In addition, statistically significant increase of absolute kidney weight was detected in the high dose females
LOEL
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: Increased in liver weight associated with histological changes.
Critical effects observed:
The toxicity of Ter-Butyl Cumyl Peroxide was investigated in rats after daily oral administration for 2 consecutive weeks at dose levels of 100, 300 and 1000 mg/kg/day. Clinical signs of toxicity, such as ataxia, tremor and salivation, were detected in the high dose group of both sexes. In addition, treatment-related microscopic changes were noted in the liver of male rats dosed at 1000 mg/kg/day.
On the basis of these results, the high dose level for subsequent toxicity studies should be less than 1000 mg/kg/day.
The toxicity of Ter-Butyl Cumyl Peroxide was investigated in rats after daily oral administration for 2 weeks, in order to select dose levels for subsequent toxicity studies. 4 Sprague-Dawley rats per sex were exposed to 0, 100, 300 and 1000 mg/kg bw/day for 14 days. No mortality occurred during the study. Ataxia, tremor and salivation were the most relevant clinical signs detected in all males and
females of the high dose group. Hunched posture and piloerection were also detected in all females of the same group. No changes of toxicological importance of body weight were observed in treated animals, compared to controls, during the study. No differences in terminal body weight were seen at the end of treatment in both sexes. There was no effect on food consumption.
A statistically significant increase of liver weights was detected in males and females dosed at = 300 mg/kg/day. In males dosed at 1000 mg/kg/day this increase was considered treatment-related, since it was correlated with histopathological changes. These changes consisted of minimal to mild increased size of hepatocytes, including nucleus and cytoplasm, localised in the centrilobular region of the hepatic lobule. Such liver change, produced following a large number of xenobiotic exposures, is considered a hallmark of enzyme induction with an increase of protein synthesis or cytoplasmic organelles.
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
Deviations:
A total of 90 Sprague Dawley SD rats (45 males and 45 virgin females), 6 to 7 weeks old and with a weight range of approximately 188 to 214 g for males and 160 to 176 g for females, were received from Charles River Italy S.p.A., Calco (Lecco), Italy.
After arrival the weight range for each sex was determined and the animals were temporarily identified within the cage by means of a coloured mark on the tail. A health check was then performed by a veterinarian.
An acclimatisation period of 13 days was allowed before the start of treatment, during which time the health status of the animals was assessed by
thorough observations.
Animal room controls were set to maintain temperature and relative humidity at 22°C +- 2°C and 55% +- 15% respectively; actual conditions were monitored, recorded and the records retained. No relevant deviations from these ranges were recorded during the study. There were approximately 15 to 20 air changes per hour and the rooms were lit by artificial light for 12 hours each day.
In-life data from 26 April 2012 to 25 June 2012
Details on exposure:
The required amount of Ter-Butyl Cumyl Peroxide was suspended in the vehicle (corn oil).
The formulations were prepared daily (concentrations of 15, 30 and 120 mg/mL) and the concentrations were calculated and expressed in terms of test item as supplied.
The formulations were gently mixed using mechanic stirrer.
Details on mating procedure:
Mating was monogamous (one male to one female). A vaginal smear was taken from the day after the start of pairing until positive identification of copulation (sperm identification, vaginal plug in situ or copulation plugs found in the cage tray).
The female was paired with the same male until positive identification occurred.
The proposed formulation procedure for the test item was checked in the range from 15 to 120 mg/mL by chemical analysis (concentration and homogeneity) during the pre-treatment period to confirm that the method was suitable. Final results for all levels were within the acceptability limits stated in RTC's SOPs for concentration (90-110%) and homogeneity (CV <10%).
In RTC Study no. 88760, stability after 24 hours at room temperature was verified in the range from 1 to 200 mg/mL. According to RTC's SOPs, suspensions are considered to be stable if concentration and homogeneity, after the defined period of storage, are still acceptable (90%-110% for concentration and CV<10% for homogeneity).
Samples of the formulations prepared on Weeks 1 and 6 were analysed to check the homogeneity and concentration. Results of the analyses were within the acceptability limits stated in RTC's SOPs for suspensions (90-110% for concentration and CV <10% for homogeneity).
Chemical analysis was carried out by the Analytical Chemistry Department at RTC according to a validated method (RTC Study No. 88760), in the range from 1 to 200 mg/mL.
Animals were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter through the day before necropsy.
Animals were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum.
Doses / concentrationsopen allclose all
Doses / concentrations 1
75 mg/kg bw/day (actual dose received)
150 mg/kg bw/day (actual dose received)
3 groups of 10 males and 10 females each . A similar constituted control group received the vehicle alone during the treatment period.
The oral route was selected as it is a possible route of exposure of the test item in man.
The dosages, selected in consultation with the Sponsor, were 75, 150 and 600 mg/kg/day.
Dose levels were selected in agreement with the Sponsor based on information from a preliminary non GLP compliant study (RTC Study No.: 88780EXT).
Parental animals: Observations and examinations:
Throughout the study, all animals were checked early in each working day and again in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
One control animal (no. 91770009) judged to be in extremis was killed.
All clinical signs were recorded for individual animals.
Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs were recorded. Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions
Clinical observations (Functional Observation Battery Tests)
Once before commencement of treatment and at least once a week thereafter, each animal was given a detailed clinical examination. Each animal was removed from the home cage and observed in an open arena. The tests included observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern).
All observations were recorded for individual animals.
Grip strength and sensory reactivity to stimuli
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group for evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli) and for assessment of grip strength. Measurements were performed using a computer generated random order. For males the tests were performed the day before necropsy and for females on Day 3 post partum.
Motor activity assessment (MA)
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group and the motor activity was measured (for approximately 5 minutes) by an automated activity recording device. Measurements were performed using a computer generated random order. For males the tests were performed the day before necropsy and for females on Day 3 post partum
Males were weighed weekly from allocation to termination.
Females were weighed weekly from allocation to pairing and on gestation Days 0, 7, 14 and 20. Dams were also weighed on Days 1 and 4 post partum.
The weight of food consumed by each cage of males and females was recorded weekly during the pre-mating period starting from allocation. Individual food consumption for the females was measured on gestation Days 7, 14 and 20 starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum.
Clinical pathology investigations
As a part of the sacrificial procedure, samples of blood were withdrawn under isofluorane anaesthesia from the abdominal vena cava from 5 males and 5 females (females with viable litters) randomly selected from each group, under condition of food deprivation.
The blood samples collected were divided into tubes as follows:
EDTA anticoagulant for haematological investigations
Heparin anticoagulant for biochemical tests
Citrate anticoagulant for coagulation tests
The measurements performed on blood samples are listed below:
Haematocrit
Haemoglobin
Red blood cell count
Reticulocyte count
Mean red blood cell volume
Mean corpuscular haemoglobin
Mean corpuscular haemoglobin concentration
White blood cell count
Differential leucocyte count
- Neutrophils
- Lymphocytes
- Eosinophils
- Basophils
- Monocytes
- Large unstained cells
Coagulation tests
Prothrombin time
Alanine aminotransferase
Aspartate aminotransferase
Gamma-glutamyltransferase
Total bilirubin
Total cholesterol
Total protein
A/G Ratio
Urinalysis (Only males)
At the same time interval as the clinical pathology investigations, individual overnight urine samples were also collected from the same animals under the same conditions. Before starting urine collection, water bottles were removed from each cage and each animal received approximately 10 mL/kg of drinking water by gavage, in order to obtain urine samples suitable for analysis.
Urobilinogen
The sediment, obtained from centrifugation at approximately 3000 rpm for 10 minutes, was examined microscopically for:
Leucocytes
Spermatozoa and precursors
Other abnormal components
Oestrous cyclicity (parental animals):
Vaginal smears were taken daily in the morning starting two weeks before pairing until a positive identification of copulation was made. The vaginal smear data were examined to determine the following:
a) anomalies of the oestrous cycle;
b) pre-coital interval (i.e., the number of nights paired prior to the detection of mating).
Sperm parameters (parental animals):
Parameters examined in [P] male parental generations:
[testis weight, epididymis weight, morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle]
Litter observations:
Parturition and gestation length
A parturition check was performed from Day 20 to Day 25 post coitum.
Gestation length was calculated as the time between the day of successful mating (Day 0 post coitum) and the day of commencement of birth (i.e. first detected presence of offspring in the cage). The day that offspring were first detected in the cage was considered Day 0 post partum.
Pups identification, weight and observation
As soon as possible after parturition was considered complete (Day 0 or 1 post partum), all pups (live and dead) were counted, sexed and live pups were identified.
Live pups were individually weighed on Days 1 and 4 post partum.
Pups killed or dying during the lactation period were weighed before the despatch to necropsy.
Observation was performed once daily for all litters.
Postmortem examinations (parental animals):
Parental animals were killed by exsanguination under isofluorane anaesthesia. All animals were subject to necropsy
Parental males:
The males were killed after the mating of all females, after 33 days of treatment.
Parental females:
The females with live pups were killed on Day 4 post partum.
The females which did not give birth 25 days after positive identification of mating were sacrificed on Days 26 or 27 post coitum.
The clinical history of the males and females of the parental generation was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices).
Changes were noted, the requisite organs weighed (excluding one animal sacrificed for humane reasons) and the required tissue samples preserved in fixative and processed for histopathological examination.
All females were examined also for the following:
a) external and internal abnormalities;
b) number of visible implantation sites (pregnant animals);
c) number of corpora lutea (pregnant animals).
Organ weights
From all animals (with the exception of animal humane killed) the organs were dissected free of fat and weighed.
The ratios of organ weight to body weight were calculated for each animal.
Tissue fixed and preserved
Samples of all the tissues listed in Annex 1 were fixed and preserved in 10% neutral buffered formalin (except eyes, optic nerves, testes and epididymides which were fixed in modified Davidson's fluid and preserved in 70% ethyl alcohol).
After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin.
In addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS). The morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed.
The examination was restricted as detailed below:
a) Tissues specified in Annex 1 from 5 males and 5 females randomly selected (animals evaluated for clinical pathology) in the control and high dose group killed at term.
b) Tissues specified in Annex 1 from all animals killed during the treatment period.
c) All females sacrificed because no delivery, to investigate possible causes.
d) All abnormalities in all groups
Postmortem examinations (offspring):
Pups were euthanised by intraperitoneal injection of Thiopenthal on Day 4 post partum
All pups found dead in the cage were examined for external and internal abnormalities (including gonadal inspection).
All live pups sacrificed at termination were killed and examined for external abnormalities and sex confirmation by gonadal inspection.
Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett's test or a modified t test, depending on the homogeneity of data.
The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
The criterion for statistical significance was p<0.05 and p<0.01.
The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.
Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov-Smirnov test if n is more than 5.
Reproductive indices:
The following reproductive indices were calculated:
Copulatory Index (%) = no. of animals mated / no. of animals paired x 100
Fertility Index (%) = no. of males which induced pregnancy / no. of males paired x 100
Fertility Index (%) = no. of pregnant females /no. of females paired x 100
Pre-coital Interval = Mean number of days between pairing and mating
Offspring viability indices:
Pre-birth loss was calculated as a percentage from the formula:
(No. of visible implantations - total litter size at birth ) / No. of visible implantations x 100
Pup loss at birth was calculated as a percentage from the formula:
(Total litter size - live litter size) / Total litter size x 100
Cumulative pup loss on Day 4 post partum was calculated as a percentage from the formula:
(Total litter size at birth - live litter size at Day 4) / Total litter size at birth x 100
Pre-implantation loss was calculated as a percentage from the formula:
(no. corpora lutea- no. implantations) / no. corpora lutea x 100
Sex ratios were calculated at birth and on Day 4 post partum and were presented as the percentage of males per litter.
Results: P0 (first parental generation)
General toxicity (P0)
See section 7.5.1.
Dermal irritation (if dermal study):
mortality observed, non-treatment-related
Description (incidence):
One mid-dose female receiving 150 mg/kg bw/day (animal no. 91770043) had total litter loss on Day 0 post partum and was sacrificed on Day 3 post partum.
The number of females with live pups on Day 4 post partum was: 9 in the control group, 10 in the low dose group (75 mg/kg bw/day), 7 each in the mid-dose (150 mg/kg bw/day) and high dose groups (600 mg/kg bw/day).
In pregnant females, the decrease in body weight in Group 4 was statistically significant during the post coitum period starting from Day 7 (approximately 6%) to Day 20 (approximately 18%) and on Day 1 post partum (approximately 15%) and Day 4 post partum (approximately 18%). Before pairing there was no effect on body weight in females although a very slight decrease, not statistically significant, was observed in Group 4 ( up to 3.6%).
In females, statistically significant decrease in body weight gain in Group 4 was recorded on days 14 and 20 post coitum (up to approximately 51%). Although not statistically significant, a trend to decrease in body weight gain was also observed in Group 2 and 3 ( up to 12.4%).
Significantly reduced food consumption was recorded in high dose pregnant females starting from Day 14 post coitum (approximately 18%) up to Day 4 post partum (approximately 35%). Although not statistically significant, a trend to decrease in food consumption was also observed in Group 3 (up to 5.6%).
effects observed, non-treatment-related
Immunological findings:
Histopathological findings: neoplastic:
Other effects:
Reproductive function / performance (P0)
Reproductive function: oestrous cycle:
The number of oestrus cycles was decreased in high dose females with respect to the control females. A trend to decrease was also observed in Groups 2 and 3. However, these values were comparable with the control historical data, therefore they were not considered to be of toxicological relevance.
Reproductive function: sperm measures:
Reproductive performance:
All females mated both in the control and treated groups.
A total of 5 females were found not pregnant at necropsy: 2 in the mid-dose group (animal nos. 91770047, 91770059) and 3 in the high dose group (animal nos. 91770065, 91770073, 91770077).
Decrease in pre-coital interval observed in high dose females was not considered to be of toxicological relevance.
The copulatory index did not show differences between treated and control groups.
Fertility index of males and females receiving the dose levels = 150 mg/kg/day was decreased compared to the control group. Although the index of 80% detected in the 150 mg/kg/day level was comparable with the historical control data
Effect levels (P0)
NOAEL
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic
reproductive performance
other: Decrease of corpora lutea
Results: F1 generation
General toxicity (F1)
Apparently no food intake (milk) and small appearance were the clinical signs generally noted in control and treated groups. In addition, cold to touch was observed in treated groups (2 litters in Group 2, 1 pup in Group 3 and 4 litters in Group 4).
Mortality / viability:
no mortality observed
Decreased litter weight was noted on Days 1 and 4post partum in the high dose group.
Sexual maturation:
No milk in stomach and autolysed organs in the abdomen and thoracic cavity were observed at necropsy in the decedent pups of control and treated groups. Most of the organs cannibalized were observed in all pups of one mid-dose female (animal no. 91770043)
Malrotated forelimb and polysyndactyly were confirmed respectively in one pup of low dose group and one pup of mid-dose group sacrificed on Day 4. These malformations were considered incidental and not treatment-related.
No abnormalities were found in all other pups of control and treated groups sacrificed on Day 4.
Histopathological findings:
Developmental neurotoxicity (F1)
Developmental immunotoxicity (F1)
Developmental immunotoxicity:
Details on results (F1)
At birth, significant reduced litter size (total and live, respectively 35% and 37%), together with a significantly reduced number of females (approximately 50%), were detected at statistical analysis in the high dose group compared to controls. However, no significant differences in sex ratio (calculated as percentage of males) were detected in the same group.
On Day 1 post partum a significantly reduced mean litter weight (46%) was found in the high dose group compared to controls.
On Day 4 post partum, live litter size, number of females and litter weight were still significantly reduced in the high dose group (respectively 50%, 63% and 54%) compared to controls and no difference in sex ratio were detected.
Cumulative % pup loss on Day 4 post partum was considerably increased in the high dose group, although without a statistical significance.
Effect levels (F1)
Generation:
other: Decrease of implantation sites
Target system / organ toxicity (F1)
Overall reproductive toxicity
Reproductive effects observed:
Lowest effective dose / conc.:
Treatment related:
Relation to other toxic effects:
reproductive effects as a secondary non-specific consequence of other toxic effects
Dose response relationship:
Any other information on results incl. tables
Day of post coitum phase
Body weight(g)
Dose levels
(mg/kg)
294.84 (+0.05%)
332.21 (-0.5%)
275.69 (-6.4%)*
303.34 (-9.2%)**
346.43 (-18.3%)**
Day of post partum phase
318.44 (+0.9%)
* group mean is significantly different from control at level p < 0.05
** group mean is significantly different from control at level p < 0.01
BODY WEIGHT GAIN
Body weightgain(g)per day
5.339 (-4.7%)
14.244 (-3.5%)
12.938 (-12.4%)
3.951 (-29.5%)**
(g/animal/day)
25.35 (+1.9%)
23.75 (-4.5%)
20.37 (-18.1%)**
21.10 (-17.9%)*
OESTRUS CYCLE
oestrus cycles
Fertility index
Precoital interval
(days)
3.4 (-5.6%)
2.7 (-25.0%)
REPRODUCTIVE PARAMETERS
Corpora Lutea
(Mean number)
Total litter
Pre-birth
5.13 (+6.4%)
1.89 (-36.1%)
6.58 (+36.5%)
9.71 (-35.3%)*
20.81 (+603.0%)
LITTER DATA
At birth
Day 1 post partum
Live litter size
Litter weight
On the basis of the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for reproductive/developmental toxicity could be considered 150 mg/kg/day.
The toxic effects on Sprague-Dawley rats of both sexes after repeated dosing with Luperox 801 (97% tert-butyl cumyl peroxide), as well as any effects of the test item on male and female reproductive performance such as gonadal function, mating behaviour, conception, parturition and development of offspring up to Day 4 post partum were evaluated in an OECD 422 study. The test item, suspended in corn oil, was administered by oral gavage to 3 groups of 10 males and 10 females each at doses of 0, 75, 150 or 600 mg/kg. Males were treated for a total of 33 days including 2 weeks prior to pairing and continuously thereafter, up to the day before necropsy. Females were treated for 2 weeks before pairing, thereafter during pairing, post coitum and lactation periods until Day 3 post partum. The following investigations were performed in all groups: body weight, clinical signs (including neurotoxicity assessment, motor activity and sensory reaction to stimuli), food consumption, oestrous cycle, mating performance, clinical pathology investigations (haematology, clinical chemistry and urinalysis), litter data, macroscopic observations, organ weights and histopathological examination. Clinical signs and macroscopic observations of pups were also performed. The parental toxicity is detailed in the section 7.5 of the IUCLID, repeated dose toxicity.
One control female judged to be in extremis was killed on post coitum Day 18. A total of 5 females were found not pregnant at necropsy: 2 in the mid-dose group and 3 in the high dose group. One mid-dose female had total litter loss on Day 0 post partum and was sacrificed on Day 3 post partum. The number of females with live pups on Day 4 post partumwas: 9 in the control group, 10 in the low dose group, 7 each in the mid-dose and high dose groups.
All females mated both in the control and treated groups. The decrease in the number of oestrus cycles and in the pre-coital interval observed in high dose females with respect to the control females were not considered of toxicological relevance. Two females in the mid-dose group and 3 females in the high dose group were found not pregnant at necropsy.The copulatory index of males and females did not show differences between treated and control groups. On the contrary, fertility index of males and females receiving the dose levels = 150 mg/kg/day was decreased compared to the control group.
Corpora lutea, implantations and total litter size were statistically decreased in the high dose females respect to the controls. In addition, an increase in pre-birth loss percentage was also detected in the same group. Gestation periods were similar in treated groups and controls.
There was no difference sex ratio. In the high dose group, decreased litter weight was noted on Day 1post partum with respect to the controls. On Day 4 post partum, live litter size, number of females and litter weight were still significantly reduced compared to controls and no difference in sex ratio were detected.
On the basis of the results obtained in the study, the NOAEL for both systemic toxicity and reproduction/developmental toxicity is considered 150 mg/kg/day for males and females. For systemic toxicity, this NOAEL is based on clinical signs, reduced body weight and bodyweight gain at 600 mg/kg/day and on kidney macroscopic and microscopic changes on male rats. For reproduction/developmental toxicity this NOAEL is based on the decrease of fertility index, decrease of corpora lutea and implantation sites, litter weight and litter size at 600 mg/kg/day.